| Febrile seizure(FS)is one of the most common pediatric neurological emergencies that are closely related to epilepsy.In children with FSs,the risk for epilepsy is about 2-10 times higher than that of the general population,and 10-15% of the epilepsy patients have a history of FSs.The FSs are also highly familial and ethnic different.In the last decades,with widely application of genetic testing in clinical practice,epileptic genetic studies have provided a lot of evidence for the close connection between FS,GEFS+ and other fever-related epilepsies on genetic backgrounds.At the same time,with the discovery of many new epilepsy related genes,the exact relationship between FS and epilepsy has also become more confounding.Further studies on distinguishing FS and epilepsies at the molecular level becomes very important and could help better understand the underlying mechanism of FS.Yet,there lack such large-population study on both clinical characteristics and genetic spectrums of FSs in China.Due to the benign prognosis of FSs,most patients only go to outpatient and emergency departments.There are heavy works in outpatient and emergency departments in China.Many hospitals lack of electronic hospital information system(HIS)in outpatient and emergency departments compared with that of the inpatient HIS systems,not even an effective long-term follow-up system.Most doctors’ knowledge of febrile seizures still stayed in the old books and past experience.Due to the lack of effective outpatient/clinic HIS system and long-term follow-up,it is difficult to well distinguish FSs who are at high risk of epilepsy,leading to a lower early recognition of fever-related epilepsy unless when they become more severe.What’s more,the important role of genetic factors in FSs,the impact of different genetic factors on prognosis and the rapid update from related researches have not been fully recognized by the majority of primary care providers.Therefore,building a multiple-center collaborative platform and a database for FSs as a common disease,carrying out epidemiological research,establishing a clinical and genetic risk assessment and predicting model system through molecular bioinformatics technics,and promoting a long-term follow-up system then verifying the risk assessment system through this long-term follow-up system,may of significant social and scientific meanings,for they may provide evidence in good clinical practice,and improve the efficiency of precise long-term management and reduce the costs.To solve the above problems from all aspects including how to establish a national-wide multi-center platform,how to promote it,how to do epidemiology studies on it,how to do genetic analysis,correlating the genotypes with phenotypes,research on the possibly molecular mechanisms and explore the future directions,we conducted a vast of work on the study.In the first part of this study,we focus on building a national-wide collaborating network and the database of cohort for the project of the gene spectrum of Chinese febrile seizures and fever-related epilepsy(China FS/FEPmap project).We collected the clinical information of FSs children and performed next-generation sequencing.The information of investigator hospitals was collected,combined with the information of the electronic CRF table,we analyzed the social factors affecting the promotion of the project in during the social practice,and we also analyzed the epidemiology of febrile seizures in China.There are still great difficulties in general NGS detecting in febrile seizure patients,mainly for the GDP and permanent population limitation.Patients with complex febrile seizures or recurrent seizures,status epilepsy,or more abnormal EEG detected,were more likely to accept a NGS detection.However,the mainly clinical characteristics were not significantly different from previous studies.The male-female ratio of children with febrile seizures in China was 1.8:1,and 85.4%of the children had the first attack between 6 months and 3 years,of which the peak age was6-18 months,58.4% was complex febrile seizures,and 47.7% had positive febrile seizure family history,73.1% of the first febrile seizures were general seizures,71.1% of the first febrile seizures were induced by respiratory infections.The number of febrile seizures were fluctuated seasonal,similar to those seasonal changes of childhood infectious diseases.9.0%of patients had vaccine-related febrile seizures,among which measles-related vaccines were the most commonly seen.In the second part of the study,we recorded the sequencing data of children with febrile seizures,applied single-gene screening procedures to find out the pathogenic genes,performed case-control association analysis using NGS data,carried out family studies based on phenotype-genotype co-segregation,performing functional research and reviewed the published population,and we outlined the genetic landscape of Chinese febrile seizures mainly due to SCN1 A and SCN9 A genes,of which mostly located on non-transmembrane domains.The ADGRV1 is a most potential febrile seizure gene,while PCDH19,WDR45 and ARHGEF9 are common sex-linked febrile seizure-related genes.Febrile seizures in WDR45 patients were more likely to occur among female patients,while ARHGEF9 is more common in male patients.In this part of the study,SLC25A12 was identified as a potential secondary pathogenic gene new to febrile seizures,while the MTHFR gene was excluded as a febrile seizure-related gene.The febrile seizure-related pathogenic genes were functional enriched in the GABA system providing the possibility of underlying molecular mechanism.The Direction-Power-Distant model can be suggested for references during clinical genetic analysis of neurological genetic diseases.In the second part of the study,TSC2 gene variants were found in febrile seizures,and a potential low-frequency medium-effect SNP(rs759602607,c.849-23G>A,P=0.0682,OR=3.06)associated to TSC2-related febrile seizures were suspected.(the SNP was not detected in the 10588 Chinese identified in the case-control association analysis),while the incidence of febrile seizures in TSC populations was not higher than that in normal populations.For dominant genetic diseases with a high proportion of de novo variants,it was difficult to identify the thermological property of a gene based on family history.Therefore,we utilized the information from a preventative real-world study of sirolimus on TSC prior to epilepsy to help with the identification of the relationship of TSC and febrile seizures in the third part of the study.In this part of the study,the first seizures,the onset of-first seizures and the prognosis of epilepsy were compared between TSC patients treated with targeting sirolimus therapy before seizures and TSC patients not treated with sirolimus before seizures.It proved that early sirolimus could reduce TSC-related burden of seizures,relieve refractory epilepsy,and improve the outcomes of TSC related epilepsy.Under these condition that sirolimus worked well on preventing TSC-related seizures,the effect of targeted therapy on febrile seizure among these TSC patients were being assessed.There was no significant difference between the registered TSC patients and TSC patients who received preventative sirolimus treatment and the TSC patients who did not receive preventative sirolimus.And the incidences were not different from that of the healthy population.However,the onset-age of febrile seizures of those TSC patients who received preventative sirolimus were delayed.In the third part of the study,we showed how information from other cohort could be utilized to provide additional information to support those genes which were hard to determine their thermological properties.Based on the practice in the third part,we promoted the 6 criteria for precising targeting genetic prevention model selection. |
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